The present invention relates to a crystal of bicalutamide having a defined form and a production method thereof.
Bicalutamide represented by the formula (I): 
(hereinafter sometimes referred to as compound of the formula (I) or compound (I) in the present specification) has been reported to be useful as a compound having an antiangrogenic action (JP-B-4-32061, U.S. Pat. No. 4,636,505 and WO01/34563). As a synthetic method of the compound of the formula (I), for example, a method comprising a reaction of 4xe2x80x2-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3xe2x80x2-trifluoromethylpropionanilide represented by the formula (3): 
(hereinafter sometimes referred to as compound of the formula (3) or compound (3)) in methylene chloride solution with m-chloroperbenzoic acid is known (Howard Tucker et al, J. Med. Chem., Vol. 31, 954-959 (1988), and WO01/28990). In this method, methylene chloride is used as a solvent. Halogenated organic solvents such as methylene chloride and the like are generally harmful for human body, and the possibility of carcinogenicity thereof has been suggested. Furthermore, they may produce dioxin during waste treatments. Halogenated organic solvents such as methylene chloride and the like are associated with the problems of economic burden for the cost of waste treatment after use, and of corrosion of incinerator used for the waste treatment.
In recent years, xe2x80x9cGreen Chemistryxe2x80x9d has been drawing attention as one of the measures for risk reduction of chemical substances, and industrial application of environmentally benign type chemical reactions (or reaction not using substances potentially harmful to human body and the environment (e.g., halogen-containing substances etc.) as much as possible, and not emitting them as much as possible) has become a very important object. From this aspect, the above-mentioned production method using methylene chloride as an organic solvent is not entirely a preferable production method of bicalutamide. Therefore, the development of a production method of bicalutamide, which is superior in environmental benignity, is desired.
In addition, the above-mentioned method uses m-chloroperbenzoic acid as an oxidizing agent. m-Chloroperbenzoic acid is highly explosive and is not preferable for industrial processes. Furthermore, m-chloroperbenzoic acid is expensive and poses an economic problem.
Accordingly, industrial practice of the above-mentioned method at a large scale gives rise to the problems not only in environmental benignity, but also safety and economic aspect, due to the use of a halogenated organic solvent as the solvent and of m-chloroperbenzoic acid as the oxidizing agent.
At the moment, as a synthetic method of bicalutamide, which is free of the use of m-chloroperbenzoic acid as an oxidizing agent, the method described in, for example, WO01/00608 is known. According to this method, compound (3) is oxidized with aqueous hydrogen peroxide as an oxidizing agent, in acetic acid or formic acid, for the synthesis of bicalutamide. Thus, this method is considered to be environmentally, economically and industrially superior. In this method, however, synthesis of precursor compound (3) requires many steps (at least 4 steps), which makes this method not an economically and industrially superior synthetic method for the total synthesis of bicalutamide. Furthermore, this method includes steps using a halogenated solvent (e.g., methylene chloride etc.) for the synthesis of compound (3). Thus, it is difficult to say that this method is sufficiently environmentally conscious.
As a synthetic method of bicalutamide free of use of m-chloroperbenzoic acid as an oxidizing agent, a method described in WO02/24638 is also known. The method described in WO02/24638 includes adding aqueous hydrogen peroxide to compound (3), cooling (e.g., xe2x88x9255xc2x0 C.) the mixture, and adding trifluoroacetic anhydride to the mixture to give bicalutamide. However, this method uses expensive trifluoroacetic anhydride as a reagent, and requires cooling when trifluoroacetic anhydride is added, and is not an economically superior method. Furthermore, because of the corrosive and hygroscopic property of trifluoroacetic anhydride, the method is unsuitable for the industrial production of bicalutamide.
Accordingly, the development of an economical and industrially practical production method of bicalutamide, which is superior in environmental benignity and safety, is desired in this field.
For efficient granulation of a crystal in the field of the production of pharmaceutical drugs, it is desirable that the form of the crystal be defined. However, the form of the crystal of bicalutamide is not defined in any of the above-mentioned references, and therefore, those of ordinary skill in the art of the production of pharmaceutical drugs strongly desire provision of bicalutamide crystals having a defined form.
It is therefore an object of the present invention to provide bicalutamide having a defined crystal form, as well as an economical and industrially practical production method of bicalutamide and a crystal thereof, which is superior in environmental benignity and safety.
As a result of intensive studies by the present inventors in an attempt to solve the above-mentioned problems, they have found that bicalutamide having high purity can be produced in a large amount by reacting a compound of the above-mentioned formula (3) with aqueous hydrogen peroxide, which is an oxidizing agent, using ethyl acetate as a solvent, in the presence of sodium tungstate (or a solvate thereof), phenylphosphonic acid and a phase transfer catalyst. This method is superior in environmental benignity, economic aspect and safety, and is industrially practicable. The present inventors have also found that mono-perphthalic acid as an oxidizing agent prepared from phthalic anhydride and hydrogen peroxide is highly effective as an oxidizing agent for oxidation of olefin to epoxide, and for oxidation of thioether to sulfone, based on which fact they have found production methods of bicalutamide and a crystal thereof, which are mainly based on oxidation reactions and which are capable of finally deriving bicalutamide, which is a sulfone, sequentially via olefin, epoxide and thioether (compound (3)) from a simple starting material, as well as the specific form of the crystal of bicalutamide, which resulted in the completion of the present invention. Accordingly, the present invention provides the following.
[1] A production method of bicalutamide represented by the formula (I): 
which comprises a step of reacting a compound represented by the formula (1): 
with mono-perphthalic acid to give a compound represented by the formula (2): 
[2] The production method of the above-mentioned [1], further comprising use of methanesulfonyl chloride.
[3] A production method of bicalutamide represented by the formula (I): 
which comprises reacting a compound represented by the formula (3): 
with mono-perphthalic acid.
[4] The production method of any of the above-mentioned [1] to [3], which comprises preparing the mono-perphthalic acid from phthalic anhydride and hydrogen peroxide.
[5] A production method of bicalutamide represented by the formula (I): 
which comprises the following Steps (A)-(C):
(A) a step of reacting a compound represented by the formula (1): 
with mono-perphthalic acid to give a compound represented by the formula (2): 
(B) a step of reacting the compound of the formula (2) obtained in Step (A) with 4-fluorothiophenol to give a compound represented by the formula (3): 
(C) a step of reacting the compound of the formula (3) obtained in Step (B) with mono-perphthalic acid to give bicalutamide.
[6] The production method of the above-mentioned [5], wherein the Step (A) further comprises use of methanesulfonyl chloride.
[7] The production method of the above-mentioned [5] or [6], which comprises a step of preparing the mono-perphthalic acid from phthalic anhydride and hydrogen peroxide.
[8] A production method of bicalutamide represented by the formula (I): 
which comprises reacting a compound represented by the formula (3): 
with aqueous hydrogen peroxide, in the presence of sodium tungstate or a solvate thereof, phenylphosphonic acid and a phase transfer catalyst, in ethyl acetate.
[9] The production method of the above-mentioned [8], wherein the amount of hydrogen peroxide to be used is a 3 to 6-fold molar amount of the compound represented by the formula (3).
[10] The production method of the above-mentioned [8] or [9], wherein the amount of sodium tungstate or a solvate thereof to be used is 0.5-5 mol % of the compound represented by the formula (3).
[11] The production method of any of the above-mentioned [8] to [10], wherein the amount of phenylphosphonic acid to be used is 0.5-5 mol % of the compound represented by the formula (3).
[12] The production method of any of the above-mentioned [8] to [11], wherein the amount of the phase transfer catalyst to be used is 0.5-5 mol % of the compound represented by the formula (3).
[13] The production method of any of the above-mentioned [8] to [12], wherein sodium tungstate or a solvate thereof is sodium tungstate dihydrate and the phase transfer catalyst is tetrabutylammonium bromide.
[14] The production method of any of the above-mentioned [1] to [13], further comprising
(I) a step of preparing a solution containing bicalutamide,
(II) a step of adding, where necessary, a hydrocarbon solvent to the solution obtained in Step (I), and
(III) a step of cooling the solution obtained in Step (I) or (II) to allow precipitation of a crystal of bicalutamide.
[15] The production method of the above-mentioned [14], wherein the Step (I) comprises concentration of a solution.
[16] The production method of the above-mentioned [15], wherein the solution is a solution of bicalutamide in ethyl acetate.
[17] The production method of the above-mentioned [14], wherein the solution obtained in Step (II) is a solution of bicalutamide in a mixed solvent of ethyl acetate and heptane.
[18] The production method of the above-mentioned [14], wherein the Steps (I)-(III) are respectively the following Steps (i)-(iii):
(i) a step of adding ethyl acetate to bicalutamide,
(ii) a step of adding, where necessary, a hydrocarbon solvent selected from hexane and heptane to the solution obtained in Step (i), and
(iii) a step of cooling the solution obtained in Step (i) or (ii) to allow precipitation of a crystal of bicalutamide.
[19] The production method of the above-mentioned [18], wherein, in Step (i), 1.0 ml-10 ml of ethyl acetate is added per 1 g of bicalutamide, and, in Step (ii), 1.5 ml-5 ml of the hydrocarbon solvent is added per 1 g of bicalutamide.
[20] The production method of the above-mentioned [18], wherein, in Step (i), 2 ml-6 ml of ethyl acetate is added per 1 g of bicalutamide, and, in Step (ii), 1.5 ml-3.5 ml of the hydrocarbon solvent is added per 1 g of bicalutamide.
[21] The production method of any of the above-mentioned [18] to [20], wherein the solution obtained in Step (i) is at 50xc2x0 C.-70xc2x0 C.
[22] The production method of any of the above-mentioned [18] to [21], wherein, in Step (ii), the hydrocarbon solvent is added at a rate of 1.0 ml/min-4.0 ml/min per 1 g of bicalutamide.
[23] The production method of any of the above-mentioned [18] to [22], wherein, in Step (iii), the solution obtained in Step (i) or (ii) is cooled to 0xc2x0 C.-30xc2x0 C.
[24] A production method of a crystal of bicalutamide, comprising the following Steps (I)-(III):
(I) a step of preparing a solution containing bicalutamide,
(II) a step of adding, where necessary, a hydrocarbon solvent to the solution obtained in Step (I), and
(III) a step of cooling the solution obtained in Step (I) or (II) to allow precipitation of a crystal of bicalutamide.
[25] The production method of the above-mentioned [24], wherein the Step (I) comprises concentration of a solution.
[26] The production method of the above-mentioned [25], wherein the solution is a solution of bicalutamide in ethyl acetate.
[27] The production method of the above-mentioned [24], wherein the solution obtained in Step (II) is a solution of bicalutamide in a mixed solvent of ethyl acetate and heptane.
[28] The production method of the above-mentioned [24], wherein the Steps (I)-(III) are respectively the following Steps (i)-(iii):
(i) a step of adding ethyl acetate to bicalutamide,
(ii) a step of adding, where necessary, a hydrocarbon solvent selected from hexane and heptane to the solution obtained in Step (i), and
(iii) a step of cooling the solution obtained in Step (i) or (ii) to allow precipitation of a crystal of bicalutamide.
[29] The production method of the above-mentioned [28], wherein, in Step (i), 1.0 ml-10 ml of ethyl acetate is added per 1 g of bicalutamide, and, in Step (ii), 1.5 ml-5 ml of the hydrocarbon solvent is added per 1 g of bicalutamide.
[30] The production method of the above-mentioned [28], wherein, in Step (i), 2 ml-6 ml of ethyl acetate is added per 1 g of bicalutamide, and, in Step (ii), 1.5 ml-3.5 ml of the hydrocarbon solvent is added per 1 g of bicalutamide.
[31] The production method of any of the above-mentioned [28] to [30], wherein the solution obtained in Step (i) is at 50xc2x0 C.-70xc2x0 C.
[32] The production method of any of the above-mentioned [28] to [31], wherein, in Step (ii), the hydrocarbon solvent is added at a rate of 1.0 ml/min-4.0 ml/min per 1 g of bicalutamide.
[33] The production method of any of the above-mentioned [28] to [32], wherein, in Step (iii), the solution obtained in Step (i) or (ii) is cooled to 0xc2x0 C.-30xc2x0 C.
[34] A crystal of bicalutamide having peaks of xcex4 at 177.08, 168.16, 164.69, 142.31, 136.58, 133.09, 124.80, 118.50, 116.16, 104.68, 75.56, 67.14 and 29.23 ppm in 13C-NMR.
[35] A crystal of bicalutamide having a particle size distribution of D10 9.5 xcexcm, D50 30.3 xcexcm and D90 65.9 xcexcm.
[36] A crystal of bicalutamide having a mean particle size of 30.3 xcexcm.
[37] A crystal of bicalutamide having peaks at 2xcex8 of 6.2, 12.3, 19.1, 23.9, 24.7 and 31.1 in X-ray diffraction.
[38] A crystal of bicalutamide having peaks at 2xcex8 of 12.18, 16.8, 18.9, 23.72 and 24.64 in X-ray diffraction.